One-Step Generation of Salt-Responsive Polyelectrolyte

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One-Step Generation Salt-Responsive Polyelectrolyte Microcapsules via Surfactant Organized Nanoscale Interfacial Complexation in Emulsions (SO NICE) Gang Duan, Martin F Haase, Kathleen J. Stebe, and Daeyeon Lee Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b01526 • Publication Date (Web): 13 Jun 2017 Downloaded from http://pubs.acs.org on June 17, 2017

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One-Step Generation of Salt-Responsive Polyelectrolyte Microcapsules via Surfactant Organized Nanoscale Interfacial Complexation in Emulsions (SO NICE) Gang Duan, Martin F. Haase†, Kathleen J. Stebe, and Daeyeon Lee* Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States KEYWORDS: polyelectrolytes, microcapsules, surfactants, triggered release, emulsions

ABSTRACT: Polyelectrolyte microcapsules are versatile compartments for encapsulation, protection, and controlled/triggered release of active agents. Conventional methods of polyelectrolyte microcapsule preparation require multiple steps or do not allow for efficient encapsulation of active agents in the lumen of the microcapsule. In this work, we present the fabrication of hollow polyelectrolyte microcapsules with a salt-responsive property based on surfactant organized nanoscale interfacial complexation in emulsions (SO NICE). In SO NICE, polyelectrolyte microcapsules are templated by water-in-oil-in-water (W/O/W) double

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emulsions. One polyelectrolyte is dissolved in the inner water droplet of the W/O/W double emulsions, whereas the second polyelectrolyte is dissolved in the organic phase by hydrophobic ion paring with an oppositely charged hydrophobic surfactant. Interfacial complexation of the two polyelectrolytes generates a few hundred-nanometer thick film at the inner water-oil interface of the W/O/W double emulsions. SO NICE microcapsules can be triggered to release their cargo by increasing the ionic strength of the solution, which is a hallmark of polyelectrolyte-based microcapsules. By enabling dissolution and interfacial complexation of polyelectrolytes in organic solvents, SO NICE widens the pallet of polymers that can be used to generate functional polyelectrolyte microcapsules with high encapsulation efficiency for applications in encapsulation and controlled/triggered release.

INTRODUCTION Microcapsules that encapsulate and release active agents are widely used in numerous fields including pharmaceutical,1-3 agriculture4,5 and cosmetics6-9. Enabling triggered (active) release of molecules such as drugs,10-14 herbicides,15,16 and pesticides17,18 from microcapsules could be especially advantageous for various applications. Polyelectrolyte complexation (i.e., association of oppositely charged polymers) provides a powerful platform to prepare microcapsules with excellent triggered release properties, because they can be dissociated via various external stimuli such as salt and pH.19-22 However, the conventional methods of polyelectrolyte microcapsule preparation typically require multiple steps or has very low encapsulation efficiency.


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(a)

(i)

(ii)

(iii)

Aqueous Organic

(b)

(i)

Middle phase

Outer phase

Inner phase

(ii)

(iii)

(iv)

(v)

Figure 1. (a) Schematics depicting PSS extraction from aqueous phase (blue) into organic phase (yellow), both procedure and illustration of interfacial ion-pairing between PSS and a doublechain surfactant DDAB are presented. (i) The aqueous and organic phases are introduced into the same containera vessel; (ii) The aqueous phase is emulsified into the organic phasemixture is vigorously agitated to form an water-in-oil emulsion; (iii) Organic organic phase with PSSDDAB ion-pairs is retrieved after phase separation. (b) Schematics of SO NICE microcapsule formation process (i) W/O/W double emulsion droplets generated via a microfluidic technique; (ii) W/O/W double emulsion droplets with PDADMAC in the inner water droplet and PSSDDAB ion-pairs in the organic shell. (iii) Interfacial complexation of PDADMAC and PSS-


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DDAB at the inner water/oil interface. (iii-v) Dewetting of the polyelectrolyte shell from the oil droplet to form a water-filled SO NICE microcapsule.

One emerging approach for one-step polyelectrolyte microcapsule generation is to exploit complexation at interfaces between two immiscible phases.23,24 For example, by dissolving a polyelectrolyte of one charge in an aqueous phase and an oppositely charged polyelectrolyte in an organic phase, the two polymers can be induced to form complex layers at the interfaces between the two phases. Introducing one liquid phase as droplets into the second phase would lead to membranes that encapsulate liquid cores. In particular, by placing two oppositely charged polyelectrolytes in the middle organic phase and inner water phases of a water-in-oil-in-water (W/O/W) double emulsion, multifunctional polyelectrolyte microcapsules can be prepared via nanoscale interfacial complexation in emulsions (NICE).25,26 This method overcomes fabrication challenges that are posed by conventional methods of polyelectrolyte microcapsule preparation.27-29

Furthermore, the use of microfluidics for double emulsion generation ensures

high encapsulation (Figure 2b,i).30-32 One major challenge in using interfacial complexation for the fabrication of polyelectrolyte microcapsules or membranes is the insolubility of many polyelectrolytes in organic solvents.33-35 Because of the low permittivity of organic solvents, counter-ions of polyelectrolytes do not dissociate readily in such media. Because of this limitation, a relatively limited number of polymers (e.g., copolymers of charged and hydrophobic repeat units or un-ionized polymers that can acquire charge such as weak polyamines) with specific structures and compositions can be used to induce microcapsule formation when oil-water based emulsions are used for polyelectrolyte microcapsule preparation.25,36,37 Thus, a new approach is needed to enable the use


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of a broad variety of polyelectrolytes, both synthetic and natural, to widen the applicability of interfacial complexation for the preparation of functional polyelectrolyte microcapsules. In this work, we introduce surfactant organized nanoscale interfacial complexation in emulsions (SO NICE) to generate salt-responsive microcapsules. The microcapsules are made of two strong polyelectrolytes. Solubilization of one polyelectrolyte in the organic phase is induced via ion pairing with hydrophobic surfactants. We show that these SO NICE microcapsules can be induced to release the encapsulated materials via changes in the ionic strength of the solution. The SO NICE method broadens the pallet of polyelectrolytes that can be used for one-step generation of multifunctional polyelectrolyte microcapsules via interfacial complexation. Moreover, the combination of ion pairing38-40 and interfacial complexation can be exploited for a number of other applications that will lead to formation of functional polyelectrolyte membranes.


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EXPERIMENTAL SECTION (a)

(b) 80%

i

% of PSS extracted into chloroform

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ii

iii

60%

40%

20%

0% 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

DDAB:SS molar ratio Figure 2. (a) PSS extraction. (i) Aqueous phase is placed on top of the chloroform phase containing DDAB; (ii) aqueous phase is emulsified into fine droplets; (iii) emulsion is broken to form two macroscopic phases, i.e. an organic phase and water. (b) Percentage of PSS that extracted into chloroform under different DDAB:SS molar ratio.

Formation

and

characterization

of

poly(sodium

4-styrenesulfonate)

(PSS)-

didecyldimethylammonium bromide (DDAB) ion-pairs. The PSS-DDAB ion-pairs are generated through mixing and stirring of aqueous and organic phases containing PSS and DDAB, respectively. 1 wt% PSS is dissolved in DI water. The aqueous phase is then added to chloroform with 1:1.5 volume ratio. DDAB is dissolved in chloroform with 0.6: 1, 0.8: 1, 1:1,


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1.2: 1, and 1.5: 1 DDAB:SS molar ratio. The mixture is vortexed vigorously and subsequently stirred with a stirring bar for 1 hour. The solution is then centrifuged for 1 hour at 4500 rpm to induce complete phase separation between the aqueous and organic phases. The concentration of residual PSS in the aqueous solution is determined using UV Vis spectroscopy. The fraction of PSS extracted into chloroform is subsequently inferred from the concentration of residual PSS in the water phase. Each data point presented in Figure 2 is average of three independent measurements. Generation and characterization of SO NICE microcapsules. SO NICE microcapsules are generated using microfluidic technique as previously reported.25 The microfluidic device is made of glass capillaries with combination of flow-focusing and co-flow geometries as shown in Figure S3. Double emulsion generation within the microfluidic device is captured using an inverted microscope (Nikon Eclipse TE200) equipped with a high-speed camera (Phantom v 7.1). We use the upright microscope (Zeiss Axio Plan 2) equipped with a digital camera (AmScope MU 1003-CK 10 MP) for bright filed imaging. All images are analyzed using ImageJ. The three liquid phases used are 1 wt% poly(diallyldimethylammonium chloride) (PDADMAC, 200,000 – 300,000 Mw, Sigma-Aldrich) and 0.001 M dodecyltrimethylammonium bromide (Sigma-Aldrich) dissolved in 0 – 0.45 M sodium chloride (NaCl, Fisher Scientific) aqueous solution as the inner phase, 0.63 wt% PSS-DDAB ion pairs in a 1:1 mixture of chloroform and butyl acetate as the middle phase, and 2 wt% polyvinyl alcohol (PVA, 13,00023,000 Mw, 87%- 89% hydrolyzed, Sigma-Aldrich) in DI water as the outer phase. The size of the double emulsion droplets as well as the organic phase thickness are controlled by adjusting the flow rates of the inner, middle, and outer phases. Generated double emulsions are collected in 2 wt% PVA solution to allow for the complete evaporation of the solvents. The collecting


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container is coated with trichloro(1H,1H,2H,2H-perfluorooctyl) silane to avoid microcapsule attachment. To characterize dried microcapsules via atomic force microscopy, microcapsules collected in 2 wt% PVA are washed with DI water for 4 to 5 times. Several drops of solution containing microcapsules are then placed on top of a silicon wafer and left to air dry at room temperature (~ 25 oC). The sample is further washed with a copious amount of DI water to make sure all residual PVA is removed. The thickness of dried microcapsules is then measured using Nano RTM AFM (Pacific Technology, Inc.) in tapping mode at room temperature. The AFM cantilever used has resonance frequency of 300 kHz under tapping mode and the scan rate is set at 1 Hz. Gwyddion (v 2.30), a scanning probe microscopy data visualization and processing software, is used for AFM image analysis. The thickness of microcapsule shell is estimated using average thickness measured over the entire microcapsule area. To incorporate fluorescence dyes for confocal microscopy, 0.1 wt% Nile red (SigmaAldrich) is dissolved in the organic phase, and 0.001wt% fluorescein sodium salt (Mw 376 Da, Sigma-Aldrich) is dissolved in the inner phase. Fluorescence images are captured using a confocal laser scanning microscope (Olymus Fluo View FV 1000). During salt responsiveness test, a circle with a radius of 30% of the microcapsules’ radius is used to monitor the central region of the microcapsules. The mean values as well as the standard deviations of the fluorescence intensity over the selected area are measured using ImageJ.


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RESULTS AND DISCUSSION We demonstrate the formation of SO NICE polyelectrolyte microcapsules with triggered release functionality using two strong polyelectrolytes, PSS and PDADMAC. Neither of these polyelectrolytes can be easily dissolved in an organic solvent. The dissolution of PSS in the organic phase is achieved by electrostatically associating (or ion pairing) PSS with DDAB in a two-phase medium. An aqueous phase containing PSS is dispersed in an organic phase with DDAB, inducing association between the two molecules at the oil-water interface and subsequent partitioning of PSS-DDAB complexes into the organic phase as schematically illustrated in Figure 1a. Subsequently, W/O/W double emulsions are generated with PDADMAC in the inner water droplet and the PSS-DDAB ion-pairs in the middle organic phase (Figure 1b). Our hypothesis is that PDADMAC and PSS-DDAB will undergo interfacial complexation at the inner water-oil interface of the W/O/W double emulsions to form microcapsules, potentially by dewetting from the organic droplets. Transfer of PSS from aqueous to organic phases via hydrophobic ion-pairing with DDAB. In NICE, polyelectrolyte microcapsules are templated with W/O/W double emulsions by dissolving one of the two polyelectrolytes in the middle organic phase and the other in the inner aqueous phase. One limitation of this method is that many polyelectrolytes are highly insoluble in organic phase due to their inability to undergo dissociation in a low permittivity medium. To enable NICE with a widely studied strong polyelectrolyte pair like PADAMAC and PSS, we test the possibility of extracting PSS into the organic phase by inducing its association with a hydrophobic cationic surfactant, DDAB. Such a process of associating a charged polymer with an oppositely charged surfactant is known as ion pairing.38-40 A unique aspect of this work is that ion pairing is performed in an


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emulsion (Figure 1a). We emulsify an aqueous solution of 1 wt% PSS in an organic phase (chloroform) with DDAB with a water-to-oil volume ratio of 1:1.5 (Figure 2a). The emulsion is vigorously stirred for 1 hour (Figure 2a, ii), and is broken by centrifuging for 1 hour to form two macroscopic phases comprising water (top) and the organic phase (bottom). The organic phase appears yellow, suggesting the extraction of PSS into the organic phase presumably due to its association with DDAB. (Figure 2a, iii). We use UV-Visible spectroscopy to determine the residual amount of PSS in the aqueous phase. A mass balance gives the fraction of PSS partitioned into the chloroform. (Supporting Information, Eq. S1) The fraction of PSS partitioned into chloroform can be controlled by changing the molar ratio of DDAB to styrene sulfonate (SS) groups of PSS as shown in Figure 2b. This method of extracting polyelectrolytes into the organic phase via ion pairing can be useful in many applications where the dissolution of highly polar/charged polyelectrolytes in non-polar media is required. To test whether PSS-DDAB in the organic phase can undergo interfacial complexation with PDADMAC in the aqueous phase, we make a macroscopic planar interface between the two solutions. We observe interfacial film formation when PSS-DDAB solution is prepared with DDAB:SS ratio of 0.6:1 and 0.8:1. However, no film formation is observed at higher DDAB:SS ratios (see Supporting Information). This finding shows that PDADMAC and PSS-DDAB can undergo complexation at the water/oil interface and that the extent of PSS-DDAB association plays a critical role in enabling this complexation process. The fact that DDAB:SS molar ratios above 0.8 do not favor PDADMAC/PSS-DDAB interfacial complexation likely indicates that an appreciable number of free sulfonate groups (i.e., those that are not associated with DDAB) are necessary for PDADMAC and PSS to undergo complexation.


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SO NICE microcapsule generation. To fabricate SO NICE microcapsules, we create waterin-oil-in-water (W/O/W) double emulsion droplets with a glass capillary microfluidic device, which enables the production of highly uniform droplets with perfect encapsulation efficiency (Figure 1b).30 PDADMAC is dissolved in the inner water phase and the PSS-DDAB ion pair is dissolved in the middle organic phase (see Supporting Information Table S2 for compositions). The outer continuous water phase contains 2 wt% PVA for double emulsion stabilization. We find that the presence of a sufficient amount of salt (NaCl) in the inner phase is crucial for stable formation of microcapsules from these double emulsions. When double emulsion droplets without any salt are allowed to undergo solvent evaporation, unstable polyelectrolyte microcapsules are formed, as shown in Figure 3a(i-v). Such microcapsules collapse and lose their integrity upon solvent removal. However, stable microcapsule formation is observed when salt is added to the inner phase as seen in Figure 3b. (a)

(b)

i

ii

iii

iv

v

i

ii

iii

iv

v

Figure 3. (PDADMAC/PSS) SO NICE microcapsules formation from double emulsions. Inner phase with no NaCl: (a-i,ii,iii,iv,v) Unstable formation of polyelectrolyte microcapsules. Inner phase with 0.2 M NaCl: (b-i) Small water droplets spontaneously appear in the initial stage. (bii) Aqueous droplets coalesce as organic solvent evaporates. (b-iii, iv) The microcapsule begins


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to dewet from the mother organic phase droplet. (b-v) A microcapsule is observed after complete organic solvent evaporation. Scale bars = 50 µm.

The salt added to the inner aqueous phase of W/O/W double emulsions may facilitate the interfacial complexation between PDADMAC and PSS-DDAB by weakening interactions between PSS and DDAB via electrostatic screening.38 Because of the polyvalency of PDADMAC

and

PSS,

the

addition

of

salt

favors

the

complexation

of

the

diallyldimethylammonium groups of PDADMAC and the sulfate groups of PSS over the ion pairing between DDAB and the sulfate groups of PSS. Thus, the enhanced complexation between PSS and PDADMAC may lead to more robust interfacial complex layer and thus more stable microcapsule formation. In addition, salt addition would also induce screening of mirror charge-induced repulsion, promoting the adsorption of PDADMAC to the inner water-oil interface.41-43 Interestingly, when 0.2 M NaCl is present in the inner aqueous phase of the W/O/W double emulsion, tiny droplets (indicated by red arrows in Figure 3bi-v) are spontaneously formed in the middle organic phase as double emulsions become microcapsules. We do not fully understand the origin of these small droplets but they seem to be associated with auto-emulsification process akin to those that have been observed in amphiphilic block copolymer-containing oil-water emulsions.44 We believe that PSS-DDAB ion pair is quite amphiphilic and therefore can induce auto-emulsification.

These tiny droplets eventually

undergo coalescence with the inner droplets, and subsequently the organic phase undergoes dewetting, resulting in the formation of polyelectrolyte microcapsules.


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(b)

(a) 0.2 M

90 80 Organic

70

Contact Angle (o)

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0.3

0.4 M

/ /

60 50

Water

/

/

40 30 20 10 0 0.1

0.2

0.3

0.4

Inner Phase NaCl concentration (M)

0.5

Figure 4. (a) Optical microscopy images of (PDADMAC/PSS) SO NICE microcapsules upon (left column) dewetting and (right column) complete removal of the solvent. Data with inner phase NaCl concentration of 0.2 M, 0.3M and 0.4M presented. Scale bar = 50 µm. (b) Three phase contact angle between SO NICE microcapsules and mother organic phase droplets as a function of inner phase NaCl concentration. 10 double emulsions are analyzed to obtain the average values for each salt concentration.γ/ : interfacial tension between water and organic phase; γ/ : interfacial tension between organic phase and complex; γ/ : interfacial tension between water and complex; θ/: three phase contact angle between SO NICE microcapsules and mother organic phase droplets.

Dewetting of the organic phase during the formation of polyelectrolyte microcapsules from double emulsions indicates that the shell formed via interfacial complexation is not fully compatible with the organic phase.25, 45, 46 The effect of salt on the dewetting phenomena in SO


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NICE is further probed by varying its concentration in the inner aqueous phase. An increase in the salt concentration leads to more significant dewetting, or higher three phase contact angles (Figure 4), which suggests that different salt concentrations likely affect the composition of the polyelectrolyte complex shell. The low contact angles at low concentrations of NaCl (< 0.3 M), for example, indicates the polyelectrolyte complex is very hydrophobic, possibly due to the significant incorporation of hydrophobic DDAB in the polyelectrolyte complex film. In contrast, increasing NaCl concentrations make the polyelectrolyte film more hydrophilic, likely by inducing dissociation between DDAB and PSS. Thus, tuning the composition of the shell by changing the salt concentration could provide a powerful method of tailoring the properties of the SO NICE microcapsule. We also observe that the polyelectrolyte microcapsules stick to the surface of glass slides but do not adhere to glass slides coated with PDADMAC. These observations strongly suggest that the surface of the microcapsules is positively charged. Characterization of SO NICE microcapsules. The thickness of the SO NICE microcapsule shell made with 0.2M NaCl in the inner phase is approximately 127± 51 nm as determined by dry-state atomic force microscopy (Figure 5a). Estimation of the shell thickness assuming a uniform shell composed of PSS, PDADMAC and DDAB yields a thickness of 104 nm, in good agreement with the experimental measurement (Supporting Information, Eq. S3, S4). A key advantage of NICE is that hydrophobic species can be incorporated into the shell by simply adding them to the organic phase of the double emulsion. We confirm that SO NICE also enables the incorporation of hydrophobic species in the shell, as evidenced by the retention of a hydrophobic dye (Nile red), which was added to the organic phase of the double emulsion, in the shell of resulting SO NICE microcapsules (Figure 5b).


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600

(a)

Height (nm)

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400 200 0 0

25

50

75

100

Distance (µm) (b)

Figure 5. (a) AFM image of dry-state (PDADMAC/PSS)0.2 SO NICE microcapsule and height profile along the blue dashed line (subscript denotes the concentration of NaCl in the inner aqueous phase). (b) Confocal laser scanning micrograph of a SO NICE microcapsule encapsulating fluorescein sodium salt (green) and Nile red (red) in the core and shell of the microcapsule, respectively. Scale bars = 50 µm.

Triggered release of SO NICE microcapsule. Polyelectrolyte microcapsules are known to have stimuli-responsive properties, which enable their applications in triggered release of active agents. We show that triggered release of the model compound, fluorescein sodium salt, from SO NICE microcapsules can be induced by adding salt to the surrounding solution. When the concentration of NaCl is increased from 0.00 M to 0.06 M, the fluorescence intensity of the microcapsule lumen drops precipitously within 100 sec, as shown in Figure 6, indicating


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triggered release, likely due to substantial changes in the shell permeability rather than capsule dissolution. The 100-sec induction time likely represents the time needed for salt diffusion after concentrated salt solution is added to the medium. Interestingly, the spherical shape of the microcapsule remains intact, as is observed in the confocal image of the shell, suggesting that substantial interactions between the two polyelectrolytes remain, thus maintaining the overall structure despite the significant change in the permeability of the shell. We also observe that under a high NaCl concentration (2.0 M), polyelectrolyte microcapsules shrink dramatically within seconds. This is comparatively a much shorter time than the fluorescein release time shown in the Figure 7. Thus, we hypothesize that the release profile of the polyelectrolyte microcapsules will vary with NaCl concentration in the surrounding aqueous medium. (a)

(b)


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Figure 6. Salt responsiveness of SO NICE microcapsules. (a) CLSM image of a (PDADMAC/PSS)0.2 SO NICE microcapsule as a function of time after NaCl is added to the solution. NaCl concentration is raised from 0 M to 0.06 M. All scale bars= 40 µm.

(b)

Fluorescence intensity at the center of SO NICE microcapsule measured as a function of time. The mean and standard deviation value are normalized by initial mean fluorescent intensity.

CONCLUSION In this work, we show that salt-responsive polyelectrolyte microcapsules can be generated in one step with strong polyelectrolytes using SO NICE. By dissolving a strong polyelectrolyte in an organic medium via ion pairing with an oppositely charged hydrophobic surfactant, W/O/W double emulsions can be used as templates for the generation of polyelectrolyte microcapsules with high encapsulation efficiency and salt responsive properties. This approach potentially widens the pallet of polyelectrolytes that can be used for functional microcapsules via SO NICE. We believe it will be possible to fabricate SO NICE microcapsules that response to other stimuli such as pH and temperature by using weak and temperature-responsive polyelectrolytes, respectively. Natural polyelectrolytes such as polysaccharides and DNA could also be used for SO NICE microcapsule generation. We hypothesize that the mechanical properties and the longterm release behavior of SO NICE microcapsules could be controlled by changing the ratio of surfactant-polyelectrolyte, which is a focus of our ongoing study. Moreover, by varying the structure of surfactants and their concentrations, the functionality and properties of SO NICE microcapsule could be potentially tailored for specific applications.


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ASSOCIATED CONTENT Supporting Information. Experimental methods and calculation, including UV Vis spectra of PSS extraction, microfluidic double emulsion generation, chemical compositions of inner, middle, outer phases, experimental results showing the macroscopic films formation at the wateroil interface, and equations for microcapsule thickness calculation, are provided.

AUTHOR INFORMATION Corresponding Author *Email: [email protected] Present Addresses † Current address: Department of Chemical Engineering, Rowan University Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources U.S. Department of Energy, Office of Basic Energy Science, Division of Materials Science (DESC0007063)

ACKNOWLEDGMENT This work was primarily supported by the Biomolecular Materials program at the U.S. Department of Energy, Office of Basic Energy Science, Division of Materials Science (DESC0007063).


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One-Step Generation of Salt-Responsive Polyelectrolyte Microcapsules via Surfactant Organized Nanoscale Interfacial Complexation in Emulsions (SO NICE) Gang Duan, Martin F. Haase, Kathleen J. Stebe and Daeyeon Lee*


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One-Step Generation of Salt-Responsive Polyelectrolyte

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